Chronic exposure to stress in the form of major adverse life events is associated with the development of disorders such as depression, anxiety and post-traumatic stress disorder and chronic fatigue syndrome. Changes in activity within the hypothalamic-pituitary-adrenal (HPA) axis are important features of these disorders and likely reflect plasticity in brain circuitry that coordinates these neuroendocrine responses with behavioral and autonomic function. Animals undergoing chronic stress exhibit many of the neuroendocrine autonomic and behavioral changes seen in individuals with disease. Using HPA activity as our primary endpoint, we have identified the posterior division of the paraventricular nucleus of the thalamus (pPVTh) as a critical mediator of HPA responses in chronically stressed rats though it does not seem to be functionally active in rats exposed to acute stress. Therefore, the pPVTh seems to control HPA activity specifically within the context of prior stress experience. In this proposal, we seek to characterize the neural circuits that mediate the primarily inhibitory effects of the pPVTh on HPA activity. The efferent projections of the pPVTh are limited and are primarily to limbic structures including the amygdala, prefrontal cortex and bed nucleus of the stria terminalis but also to a hypothalamic region that can more directly control HPA activity. Our general hypothesis is that the pPVTh exerts its influence through changing activity in limbic structures but not hypothalamic structures since limbic regions are more capable of evaluating sensory information within the context of past stress history. More specifically, we will determine whether the pPVTh can exert its inhibitory influence on HPA activity by acting on limbic GABA-ergic systems (Aim 1) and/or by serving as a site of negative feedback effects of glucocorticoids released by the chronic stress exposure (Aim 2). Aim 3 focuses on the pathways through which cholecystokinin released within the pPVTh alters HPA activity specifically in chronically stressed rats and Aim 4 will examine how central CRF systems interact with the pPVTh and its associated limbic circuitry. Given the specificity of pPVTh effects to the chronic stress state, characterizing this pPVTh-limbic circuitry is fundamental to understanding the association between chronic stress and changes in physiology and behavior that can lead to disease.